Salmonella enterica serovar Typhimurium ST313 sublineage 2.2 has emerged in Malawi with a characteristic gene expression signature and a fitness advantage

• DOI: 10.1093/femsml/uqae005
• Publication Date: 2024-03-27T18:34:17Z
• Authors: Benjamin Kumwenda; Rocío Canals; Alexander V Predeus; Xiaojun Zhu; Carsten Kröger; Caisey Pulford; Nicolas Wenner; Lizeth Lacharme Lora; Yan Li; Siân V Owen; Dean Everett; Karsten Hokamp; Robert S Heyderman; Philip M Ashton; Melita A Gordon; Chisomo L Msefula; Jay C D Hinton
• Keywords: Geometry; FOS: Health sciences; Gene; Microbiology; Agricultural and Biological Sciences; Serotype; Endocrinology; Salmonella; Biochemistry, Genetics and Molecular Biology; Virology; Health Sciences; Genetics; FOS: Mathematics; Pathogenicity; Biology; Dynamics and Pathogenesis of Cholera Bacteria; Signature (topology); Bacteria; Life Sciences; Gastrointestinal Viral Infections and Vaccines Development; Salmonella enterica; Global Burden of Foodborne Pathogens; Infectious Diseases; FOS: Biological sciences; Medicine; Mathematics; Research Article; Food Science

Abstract Invasive non-typhoidal Salmonella (iNTS) disease is a serious bloodstream infection that targets immune-compromised individuals, and causes significant mortality in sub-Saharan Africa. Salmonella enterica serovar Typhimurium ST313 causes the majority of iNTS in Malawi. We performed an intensive comparative genomic analysis of 608 S. Typhimurium ST313 isolates dating between 1996 and 2018 from Blantyre, Malawi. We discovered that following the arrival of the well-characterized S. Typhimurium ST313 lineage 2 in 1999, two multidrug-resistant variants emerged in Malawi in 2006 and 2008, designated sublineages 2.2 and 2.3, respectively. The majority of S. Typhimurium isolates from human bloodstream infections in Malawi now belong to sublineages 2.2 or 2.3. To understand the emergence of the prevalent ST313 sublineage 2.2, we studied two representative strains, D23580 (lineage 2) and D37712 (sublineage 2.2). The chromosome of ST313 lineage 2 and sublineage 2.2 only differed by 29 SNPs/small indels and a 3 kb deletion of a Gifsy-2 prophage region including the sseI pseudogene. Lineage 2 and sublineage 2.2 had distinctive plasmid profiles. The transcriptome was investigated in 15 infection-relevant in vitro conditions and within macrophages. During growth in physiological conditions that do not usually trigger S. Typhimurium SPI2 gene expression, the SPI2 genes of D37712 were transcriptionally active. We identified down-regulation of flagellar genes in D37712 compared with D23580. Following phenotypic confirmation of transcriptomic differences, we discovered that sublineage 2.2 had increased fitness compared with lineage 2 during mixed growth in minimal media. We speculate that this competitive advantage is contributing to the emergence of sublineage 2.2 in Malawi.